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Funduscopy photographs of (A) individual 09 of family 61043 (unaffected, 64-year-old obligate carrier), (B) individual 10 of family 61043 (unaffected, 59-year-old obligate carrier), (C) individual 11 of family 61043 (affected, 27 years old), (D) individual 13 of family 61043 (affected, 23 years old), (E) individual 07 of family 61006 (unaffected, 59year-old obligate carrier) and (F) individual 12 of family 61006 (affected, 19 years old).
Source publication
To localize and identify the gene and mutations causing autosomal recessive retinitis pigmentosa in three consanguineous Pakistani families.
Blood samples were collected and DNA was extracted. A genome-wide scan was performed by using 382 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members, and lod scores w...
Contexts in source publication
Context 1
... affected individuals examined in all three families fit the diagnostic criteria for RP, as described herein. Fundus photo- graphs of affected individuals showed changes typical in RP, including a waxy, pale optic disc, attenuation of retinal arter- ies, and bone-spicule pigment deposits in the midperiphery of the retina (Figs. 1C, 1D, 1F). Unaffected parents did not show any funduscopic signs of RP (Figs. 1A, 1B, 1E). Neither atten- uation of retinal arteries nor presence of bone-spicule pigment deposits in the midperiphery of the retina was observed in unaffected individuals, although some older individuals showed mild atrophic changes in the peripheral retina (Fig. 1A, individual 09 of family 61043, 64 years old). No unaffected individuals in these families reported night blindness. Affected individuals had typical RP changes on ERG, including loss of both the rod and cone responses, whereas the parents showed no changes consistent with RP (Fig. ...
Context 2
... affected individuals examined in all three families fit the diagnostic criteria for RP, as described herein. Fundus photo- graphs of affected individuals showed changes typical in RP, including a waxy, pale optic disc, attenuation of retinal arter- ies, and bone-spicule pigment deposits in the midperiphery of the retina (Figs. 1C, 1D, 1F). Unaffected parents did not show any funduscopic signs of RP (Figs. 1A, 1B, 1E). Neither atten- uation of retinal arteries nor presence of bone-spicule pigment deposits in the midperiphery of the retina was observed in unaffected individuals, although some older individuals showed mild atrophic changes in the peripheral retina (Fig. 1A, individual 09 of family 61043, 64 years old). No unaffected individuals in these families reported night blindness. Affected individuals had typical RP changes on ERG, including loss of both the rod and cone responses, whereas the parents showed no changes consistent with RP (Fig. ...
Context 3
... affected individuals examined in all three families fit the diagnostic criteria for RP, as described herein. Fundus photo- graphs of affected individuals showed changes typical in RP, including a waxy, pale optic disc, attenuation of retinal arter- ies, and bone-spicule pigment deposits in the midperiphery of the retina (Figs. 1C, 1D, 1F). Unaffected parents did not show any funduscopic signs of RP (Figs. 1A, 1B, 1E). Neither atten- uation of retinal arteries nor presence of bone-spicule pigment deposits in the midperiphery of the retina was observed in unaffected individuals, although some older individuals showed mild atrophic changes in the peripheral retina (Fig. 1A, individual 09 of family 61043, 64 years old). No unaffected individuals in these families reported night blindness. Affected individuals had typical RP changes on ERG, including loss of both the rod and cone responses, whereas the parents showed no changes consistent with RP (Fig. ...
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Retinitis pigmentosa is a genetically heterogeneous form of retinal degeneration that affects approximately 1 in 3500 people worldwide. Recently we identified the gene responsible for the RP1 form of autosomal dominant retinitis pigmentosa (adRP) at 8q11-12 and found two different nonsense mutations in three families previously mapped to 8q. The RP...
We identified three distinct mutations and six mutant alleles in GDAP1 in three families with axonal Charcot-Marie-Tooth (CMT) neuropathy and vocal cord paresis, which were previously linked to the CMT4A locus on chromosome 8q21.1. These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both a...
Citations
... The RP1 locus was first identified in 1982 in a large family with AD RP [31], and the gene linked to the disease was named retinitis pigmentosa 1 (RP1, OMIM 603937) [32], which is now known to be one of the most frequent causative genes in AD RP, with a prevalence as high as 10% [33]. Later publications revealed that variants in RP1 can also cause AR RP [34][35][36], and a recent study depicted that mutations in this gene are a relatively common cause of AR RCD [37]. ...
Retinitis pigmentosa (RP) is the most common inherited retinal disease (IRD), with a worldwide prevalence of about 1:4000. Functionally, RP is a rod-cone dys-trophy (RCD), where rod photoreceptors are affected earlier and more severely than cone photoreceptors. As a consequence, RP typically manifests with night blindness beginning in adolescence followed by concentric constriction of visual field, while central visual loss usually occurs later in life. The molecular bases of this disorder, however, are highly heterogeneous, with over 100 genes implicated, and in some RP subtypes macular manifestations occur relatively early in the disease course. The subsequent rapid decline in visual acuity in such patients blurs the line between RP and other IRDs, namely cone-rod dystrophies (CORDs), and increases the difficulty in narrowing down the differential diagnosis. This chapter aims to review the features of non-syndromic RP caused by mutations in genes that have been commonly associated with early macular involvement and to provide an updated overview on recent preclinical or clinical studies addressing these rare diseases.
... Retinitis pigmentosa (RP) is a retinal degenerative and inherited blinding disease with a prevalence of approximately 1 in 4000 individuals worldwide, which is manifested by initially a loss of night vision and progressively end up with complete blindness [1][2][3]. To date, mutations in around 100 genes have been reported associated with RP by different inherited manners including autosomal recessive, autosomal dominant, and X-linked inheritance [4][5][6]. Multiple molecular mechanisms have been shown to be involved in the pathogenesis of RP such as genetic aberrance, autoimmunity and autophagy [7][8][9]. Genetic defect causing retinal degeneration increases the photoreceptor fragility to light, meanwhile, excessive light exposure evokes the photoreceptor apoptosis, therefore, the retinal light damage mice model has been widely used to study pathogenesis of neurodegenerative retinal diseases including RP [10][11][12]. ...
Background
Neurodegenerative retinal diseases such as retinitis pigmentosa are serious disorders that may cause irreversible visual impairment. Ferroptosis is a novel type of programmed cell death, and the involvement of ferroptosis in retinal degeneration is still unclear. This study aimed to investigate the related ferroptosis genes in a mice model of retinal degeneration induced by light damage.
Methods
A public dataset of GSE10528 deriving from the Gene Expression Omnibus database was analyzed to identify the differentially expressed genes (DEGs). Gene set enrichment analysis between light damage and control group was conducted. The differentially expressed ferroptosis-related genes (DE-FRGs) were subsequently identified by intersecting the DEGs with a ferroptosis genes dataset retrieved from the FerrDb database. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were further performed using the DE-FRGs. A protein-protein interaction (PPI) network was constructed to identify hub ferroptosis-related genes (HFRGs). The microRNAs (miRNAs)-HFRGs, transcription factors (TFs)-HFRGs networks as well as target drugs potentially interacting with HFRGs were analyzed utilizing bioinformatics algorithms.
Results
A total of 932 DEGs were identified between the light damage and control group. Among these, 25 genes were associated with ferroptosis. GO and KEGG analyses revealed that these DE-FRGs were mainly enriched in apoptotic signaling pathway, response to oxidative stress and autophagy, ferroptosis, necroptosis and cytosolic DNA-sensing pathway. Through PPI network analysis, six hub ferroptosis-related genes (Jun, Stat3, Hmox1, Atf3, Hspa5 and Ripk1) were ultimately identified. All of them were upregulated in light damage retinas, as verified by the GSE146176 dataset. Bioinformatics analyses predicated that 116 miRNAs, 23 TFs and several potential therapeutic compounds might interact with the identified HFRGs.
Conclusion
Our study may provide novel potential biomarkers, therapeutic targets and new insights into the ferroptosis landscape in retinal neurodegenerative diseases.
... Mutations in the RP1 gene are an important cause of both autosomal dominant and recessive forms of retinal dystrophy. [1][2][3][4] The RP1 gene itself comprises 4 exons -3 of which are coding -in which the terminal exon is the largest and encodes over 80% of the RP1 protein, a microtubule associated protein. As might be expected, most reported mutations lie within this exon. ...
Purpose
To report on the presence of autosomal dominant and compound dominant-null RP1-related retinitis pigmentosa in the same non-consanguineous family.
Observation
The father was minimally symptomatic and referred by his optometrist aged 38. He was diagnosed with rod-cone dystrophy, confirmed to be caused by the previously reported RP1 c.2613dupA mutation. He was reassured that his 11-year-old daughter had a 50% chance of inheriting the same mutation and that the condition, if she had it, would most likely be similar. Clinical phenotyping of his daughter however revealed an early onset cone-rod dystrophy. The mother was entirely asymptomatic and clinically normal. Sanger sequencing of the RP1 gene in the daughter confirmed the presence of biallelic mutations – the dominant c.2613dupA variant from her father and a c.3843dupT truncating variant inherited from her mother, both located in exon 4 of the RP1 gene. The maternal c.3843dupT has previously been reported.
Conclusions and importance
Pathogenic variants in exon 4 of RP1 are known to cause differential dominant and recessive disease. The presence of both phenotypes in a single family has not yet been reported. The father, being minimally symptomatic, is affected by a known dominant variant which truncates the RP1 protein more proximally. However, inheritance of both variants in a compound heterozygous state in the daughter resulted in a much more severe, early onset cone-rod phenotype in a pattern akin to recessive disease. This raises challenges for genetic counselling and development of gene-based therapies for RP1 mutations.
... A higher prevalence of rare hereditary diseases caused by homozygous mutations in AR genes has been observed among members of consanguineous families compared to those of non-consanguineous families [19,20]. Several studies have also reported genetic causes of IRDs among consanguineous families worldwide, especially in the areas where consanguinity rate is particularly high [21][22][23][24]. ...
Background
Consanguineous families have a relatively high prevalence of genetic disorders caused by bi-allelic mutations in recessive genes. This study aims to evaluate the effectiveness and efficiency of a consanguinity-based exome sequencing approach to capturing genetic mutations in inherited retinal dystrophy families with consanguineous marriages.
Methods
Ten unrelated consanguineous families with a proband affected by inherited retinal dystrophy were recruited in this study. All participants underwent comprehensive ophthalmic examinations. Whole exome sequencing was performed, followed by a homozygote-prior strategy to rapidly filter disease-causing mutations. Bioinformatic prediction of pathogenicity, Sanger sequencing and co-segregation analysis were carried out for further validation.
Results
In ten consanguineous families, a total of 10 homozygous mutations in 8 IRD genes were identified, including 2 novel mutations, c.1654_1655delAG (p. R552Afs*5) in gene FAM161A in a patient diagnosed with retinitis pigmentosa, and c.830T > C (p.L277P) in gene CEP78 in a patient diagnosed with cone and rod dystrophy.
Conclusion
The genetic etiology in consanguineous families with IRD were successfully identified using consanguinity-based analysis of exome sequencing data, suggesting that this approach could provide complementary insights into genetic diagnoses in consanguineous families with variant genetic disorders.
... Subsequent linkage analysis and screening for pathogenic variants revealed the identification of an RP1 null variant in ~3% of ADRP cases in North America (Pierce et al., 1999;Sullivan et al., 1999). Later on, linkage analyses of consanguineous Pakistani families revealed a homozygous recessive RP1 variant in ARRP families (Khaliq et al., 2005;Riazuddin et al., 2005) and later on, a homozygous recessive RP1 pathogenic variant was identified in an Indonesian family (Siemiatkowska et al., 2012). Analysis of 250 RP1 variants reported in ADRP and ARRP cases revealed three separate regions (the N-terminal p.1-p.613, the middle portion p.661-p.917 and the C-terminal p.939-p.2157). ...
Inherited retinal diseases (IRDs) are a clinically complex and heterogenous group of visual impairment phenotypes caused by pathogenic variants in at least 277 nuclear and mitochondrial genes, affecting different retinal regions, and depleting the vision of affected individuals. Genes that cause IRDs when mutated are unique by possessing differing genotype-phenotype correlations, varying inheritance patterns, hypomorphic alleles, and modifier genes thus complicating genetic interpretation. Next-generation sequencing has greatly advanced the identification of novel IRD-related genes and pathogenic variants in the last decade. For this review, we performed an in-depth literature search which allowed for compilation of the Global Retinal Inherited Disease (GRID) dataset containing 4798 discrete variants and 17,299 alleles published in 31 papers, showing a wide range of frequencies and complexities among the 194 genes reported in GRID, with 65% of pathogenic variants being unique to a single individual. A better understanding of IRD-related gene distribution, gene complexity, and variant types allow for improved genetic testing and therapies. Current genetic therapeutic methods are also quite diverse and rely on variant identification, and range from whole gene replacement to single nucleotide editing at the DNA or RNA levels. IRDs and their suitable therapies thus require a range of effective disease modelling in human cells, granting insight into disease mechanisms and testing of possible treatments. This review summarizes genetic and therapeutic modalities of IRDs, provides new analyses of IRD-related genes (GRID and complexity scores), and provides information to match genetic-based therapies such as gene-specific and variant-specific therapies to the appropriate individuals.
... The structure of the Pakistani population is unique with endogamous sub-populations of multi-ethnic origin and high consanguinity in each of these populations [88][89][90]. Our earlier studies on 208 multigenerational pedigrees from the same region with a diagnosis of recessive IRD [7, [91][92][93][94][95][96][97][98][99][100][101][102][103][104] found homozygous causative mutations in 149 pedigrees (~71%). So far, mutations in novel genes were observed in only five (2.5%) unrelated Pakistani pedigrees in our cohort ASRGL1 [99], IFT43 [104], ZNF513 [105], SLC24A1 [106], and CLCC1 [93]) while the remaining resolved pedigrees (97.5%) had mutations in known IRD genes. ...
Patients with inherited retinal dystrophies (IRDs) were recruited from two understudied populations: Mexico and Pakistan as well as a third well-studied population of European Americans to define the genetic architecture of IRD by performing whole-genome sequencing (WGS). Whole-genome analysis was performed on 409 individuals from 108 unrelated pedigrees with IRDs. All patients underwent an ophthalmic evaluation to establish the retinal phenotype. Although the 108 pedigrees in this study had previously been examined for mutations in known IRD genes using a wide range of methodologies including targeted gene(s) or mutation(s) screening, linkage analysis and exome sequencing, the gene mutations responsible for IRD in these 108 pedigrees were not determined. WGS was performed on these pedigrees using Illumina X10 at a minimum of 30X depth. The sequence reads were mapped against hg19 followed by variant calling using GATK. The genome variants were annotated using SnpEff, PolyPhen2, and CADD score; the structural variants (SVs) were called using GenomeSTRiP and LUMPY. We identified potential causative sequence alterations in 62 pedigrees (58%), including 41 novel and 53 reported variants in IRD genes. For 58 of these pedigrees the observed genotype was consistent with the initial clinical diagnosis, the remaining 4 had the clinical diagnosis reclassified based on our findings. In eight pedigrees (13%) we observed atypical causal variants, i.e. unexpected genotype(s), including 5 pedigrees with causal variants in more than one IRD gene within all affected family members, one pedigree with intrafamilial genetic heterogeneity (different affected family members carrying causal variants in different IRD genes), one pedigree carrying a dominant causative variant present in pseudo-recessive form due to consanguinity and one pedigree with a de-novo variant in the affected family member. Combined atypical and large structural variants contributed to about 21% of cases. Among the novel mutations, 75% were detected in Mexican and 53% found in European American pedigrees and have not been reported in any other population while only 20% were detected in Pakistani pedigrees and were not previously reported. The remaining novel IRD causative variants were listed in gnomAD but were found to be very rare and population specific. Mutations in known IRD associated genes contributed to pathology in 63% Mexican, 60% Pakistani and 48% European American pedigrees analyzed. Overall, contribution of known IRD gene variants to disease pathology in these three populations was similar to that observed in other populations worldwide. This study revealed a spectrum of mutations contributing to IRD in three populations, identified a large proportion of novel potentially causative variants that are specific to the corresponding population or not reported in gnomAD and shed light on the genetic architecture of IRD in these diverse global populations.
... There are three types of inheritance: autosomal recessive, dominant, and sex-linked recessive [73]. The autosomal recessive inheritance is the most prevalent, followed by the dominant and the sex-linked recessive inheritance [74]. Currently, it is believed that the autosomal dominant genetic type has at least 17 gene loci located on the short arm of chromosome 1 and the long arm of chromosome 3 [75]. ...
Retinitis pigmentosa (RP) is a leading cause of inherited retinal degeneration, with more than 60 gene mutations. Despite the genetic heterogenicity, photoreceptor cell damage remains the hallmark of RP pathology. As a result, RP patients usually suffer from reduced night vision, loss of peripheral vision, decreased visual acuity, and impaired color perception. Although photoreceptor cell death is the primary outcome of RP, the underlying mechanisms are not completely elucidated. Ferroptosis is a novel programmed cell death, with characteristic iron overload and lipid peroxidation. Recent studies, using in vitro and in vivo RP models, discovered the involvement of ferroptosis-associated cell death, suggesting a possible new mechanism for RP pathogenesis. In this review, we discuss the association between ferroptosis and photoreceptor cell damage, and its implication in the pathogenesis of RP. We propose that ferroptotic cell death not only opens up a new research area in RP, but may also serve as a novel therapeutic target for RP.
... However, 17 truncated variants have also been located within the hotspot region in patients with AR-RP [14,15,25,41,43,[46][47][48]. These truncated variants might underlie the loss of function responsible for AR-RP [44,49]. In the current study, one of five patients with AR-RP carried the heterozygous Alu element insertion, with the p.Met500ValfsTer7 variant, located within the hotspot region, in the other allele (Family 16-II:2 JU1464) ( Figure 1). ...
Background:
Little is known about genotype-phenotype correlations of RP1-associated retinal dystrophies in the Japanese population. We aimed to investigate the genetic spectrum of RP1 variants and provide a detailed description of the clinical findings in Japanese patients.
Methods:
In total, 607 patients with inherited retinal diseases were examined using whole-exome/whole-genome sequencing (WES/WGS). PCR-based screening for an Alu element insertion (c.4052_4053ins328/p.Tyr1352AlafsTer9) was performed in 18 patients with autosomal-recessive (AR)-retinitis pigmentosa (RP) or AR-cone dystrophy (COD)/cone-rod dystrophy (CORD), including seven patients with heterozygous RP1 variants identified by WES/WGS analysis, and 11 early onset AR-RP patients, in whom no pathogenic variant was identified. We clinically examined 25 patients (23 families) with pathogenic RP1 variants, including five patients (five families) with autosomal-dominant (AD)-RP, 13 patients (11 families) with AR-RP, and seven patients (seven families) with AR-COD/CORD.
Results:
We identified 18 pathogenic RP1 variants, including seven novel variants. Interestingly, the Alu element insertion was the most frequent variant (32.0%, 16/50 alleles). The clinical findings revealed that the age at onset and disease progression occurred significantly earlier and faster in AR-RP patients compared to AD-RP or AR-COD/CORD patients.
Conclusions:
Our results suggest a genotype-phenotype correlation between variant types/locations and phenotypes (AD-RP, AR-RP, and AR-COD/CORD), and the Alu element insertion was the most major variant in Japanese patients with RP1-associated retinal dystrophies.
... The RP1 protein, 2156 amino acids, is considered to play a role in the structural maintenance of the connecting cilia and/or possibly involved in the exchange of proteins between inner and outer sections of photoreceptor cell (24). Though the majority of the reports have shown that mutations present in the RP1 gene are associated with the autosomal dominant retinitis pigmentosa (adRP) (25-28) but many recent studies have also revealed an association of RP1 mutations with autosomal recessive retinitis pigmentosa (arRP) (12,(29)(30)(31)(32)(33)(34)(35)(36). Conte and colleagues (2003) first described RP1L1 (Retinitis pigmentosa 1-like 1) as a candidate gene for retinal degenerations. ...
... Most of the mutations reported in the RP1 gene results in adRP, however, some homozygous mutations have also been reported to cause arRP where heterozygous parents did not show RP features. The exact mechanism of disease manifestation in adRP (where the heterozygous mutation is sufficient to generate phenotype) is not yet completely understood (34,53). Dominant negative or toxic gain-of-function are the suggested underlying mechanism leading to dominant RP as a result of mutation of the RP1 protein (12). ...
Background: Retinitis pigmentosa (RP) is a heterogeneous group of ocular dystrophy. It is challenging to identify the underlying genetic defect in individuals with RP due to huge genetic heterogeneity. This study was designed to delineate the genetic defect(s) underlying RP in extended Saudi families and to describe the possible disease mechanism.
Materials and Methods: Fundus photography and a high definition optical coherence tomography (HD-OCT) were performed in order to detect the earlier stages of macular degeneration. Genomic DNA was extracted followed by genome-wide SNP genotyping and whole exome sequencing (WES). Exome data was filtered to identify the genetic variant(s) of interest.
Results: Clinical examination showed that affected individuals manifest key features of RP. The fundus exam shows pale optic disc and bone spicules at the periphery. OCT shows macular degeneration as early as at the age of 4 years. Whole genome scan by SNPs identified multiple homozygous regions. WES identified a 10 bps novel insertion mutation (c.3544_3545insAGAAAAGCTG; p.Ala1182fs) in the RP1 gene in both affected individuals of family A. Affected individual from family B showed a large insertion of 48 nucleotides in the coding part of the RP1L1 gene (c.3955_3956insGGACTAAAGTAATAGAAGGGCTGCAAGAAGAGAGGGTGCAGTTAGAGG; p.Ala1319fs). Sanger sequencing validates the autosomal recessive inheritance of the mutations.
Conclusion: The results strongly suggest that the insertion mutations in the RP1 and RP1L1 genes are responsible for the retinal phenotype in affected individuals from two families. Heterozygous individuals are asymptomatic carriers. We propose that the protective allele in other homozygous regions in heterozygous carriers contribute to the phenotypic variability in asymptomatic individuals.
... This allelic location-dependent difference in disease is seen in other genes that cause both dominant and recessive disease, including those caused by RHO and RP1. As such, this topic is a source of interest as treatment of dominant negative mutations presents a different challenge than the gene supplementation typically used to treat recessive loss-of-function disease [33]. Further studies are needed to correlate the effects of protein change on the phenotype seen in this condition. ...
Background:
Mutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-function mutations are known to cause Crisponi or Bohring-Opitz like cold induced sweating syndrome-3 (BOS-3). In this study, the phenotype and progression of five unrelated patients with KLHL7 mediated autosomal dominant RP (adRP) are characterized. Clinical evaluation of these patients involved a complete ophthalmic exam, full-field electroretinography (ffERG), and imaging, including fundus photography, spectral domain optical coherence tomography (SD-OCT), short wavelength fundus autofluorescence (SW-AF), and near-infrared fundus autofluorescence (NIR-AF). Molecular diagnoses were performed using whole-exome sequencing or gene panel testing. Disease progression was monitored in three patients with available data for a mean follow up time of 4.5 ± 2.9 years. Protein modeling was performed for all variants found in this study in addition to those documented in the literature for recessive loss-of-function alleles causing Crisponi or Bohring-Opitz like cold-induced sweating syndrome.
Results:
Genetic testing in three patients identified two novel variants within the 3-box motif of the BACK domain: c.472 T > C:p.(Cys158Arg) and c.433A > T:p.(Asn145Tyr). Clinical imaging demonstrated hyperautofluorescent ring formation on both SW-AF and NIR-AF in three patients, with diffuse peripheral and peripapillary atrophy seen in all but one case. SD-OCT demonstrated a phenotypic spectrum, from parafoveal atrophy of the outer retina with foveal sparing to widespread retinal thinning and loss of photoreceptors. Incidence of cystoid macular edema was high with four of five patients affected. Protein modeling of dominant alleles versus recessive loss-of-function alleles showed dominant alleles localized to the BTB and BACK domains while recessive alleles were found in the Kelch domain.
Conclusions:
We report the phenotype in five patients with KLHL7 mediated adRP, two novel coding variants, and imaging biomarkers using SW-AF and NIR-AF. These findings may influence future gene-based therapies for adRP and pave the way for mechanistic studies that elucidate the pathogenesis of KLHL7-mediated RP.
